CN105693693A - Preparation of pyrrole gastric acid secretion inhibitor compound salt - Google Patents
Preparation of pyrrole gastric acid secretion inhibitor compound salt Download PDFInfo
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Abstract
Belonging to the technical field of chemical drugs, the invention in particular relates to a 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methyl ammonia inorganic acid salt or organic acid salt compound with the effect of treating gastric acid related diseases. The invention makes water solubility and stability study on related salt compounds, also provides a preparation method of corresponding salts, and performs crystal form study on 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methyl ammonia acetate.
Description
Technical field
The invention belongs to chemicals technical field, be specifically related to 5-(2-fluorophenyl) preparation method of-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia inorganic acid salt or acylate and water solublity, stability and corresponding salt。
Background technology
Gastric acid related disease is a class disease most commonly seen in digestive system disease, refer to that a class is due to gastroxia, or gastric acid is especially sensitive and that the cause general name of a class digestive tract disease, common are gastroesophageal reflux disease, the digestive system disease that peptic ulcer, Zollinger-Ellison Syndrome and non-steroidal anti-inflammatory drug cause。PPI is the class medicine that current Acidinhibitor is the strongest, such as omeprazole, lansoprazole, pantoprazole, rabeprazole etc.。Owing to PPI also exists nocturnal acid rebound phenomenon, thus affecting therapeutic effect。The appearance of potassium ion competitive type acid blocker (P-CAB) class medicine solves this problem well, by competitive type inhibitor proton pump (H+, ATPase) in K+And work, can obviously reduce the generation of nocturnal acid knock-on clinically, this type of medicine includes: TAK438, Revaprazan (Revaprazan) etc.。
TAK438(5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia fumarate) be Takeda Pharmaceutical Company Limited develop a kind of potassium ion competitiveness acid blocker (P-CAB); experiment in vitro research shows this compound inhibitor proton pump (H+; ATPase) ability is 400 times of lansoprazole; can effective gastric acid secretion inhibiting; the advantage with persistent period length; but the poorly water-soluble of this compound; animal oral administration biaavailability only 10%, limits this compound and plays its acid suppression and the effect for the treatment of gastric acid related disease。
Summary of drawings
Fig. 1: 5-(2-fluorophenyl of the present invention)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia acetate XRPD spectrogram。
Fig. 2: 5-(2-fluorophenyl of the present invention)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia acetate DSC spectrogram。
Fig. 3: 5-(2-fluorophenyl of the present invention)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia acetate IR spectrogram。
Fig. 4: 5-(2-fluorophenyl of the present invention)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia acetate TG spectrogram。
Summary of the invention
Present invention aim at, overcome the deficiencies in the prior art, provide water solublity and the good 5-(2-fluorophenyl of stability)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia acetate and 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia sulfate, and to 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia acetate biological activity measured, support is provided for later dosage form research, thus more effective treatment gastric acid related disease, meet different clinical application demands。
The technical scheme is that and disclose the 5-(2-fluorophenyl with general formula)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia acylate or inorganic acid salt。
In formula, n is 1 or 1/2, HA is organic acid or mineral acid
Its described organic acid is: methanesulfonic acid, acetic acid, phosphoric acid, sulphuric acid, L MALIC ACID, citric acid, hydrochloric acid。
The preparation method that the present invention provides above-mentioned acylate, the method comprises the following steps:
Method one (acid is except liquid hydrochloric acid): by 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia and ethyl acetate, and under agitation dissolve (generally every gram of unhindered amina 4-8mL), at room temperature (10-25 DEG C), corresponding acid (unhindered amina is 1:1.05 with corresponding sour mol ratio) is added drop-wise in reaction system, add isopropanol (generally every gram of unhindered amina 3-5mL), and stir 30 minutes at such a temperature, after system temperature is down to 3-6 DEG C, stirring stirring 30 minutes, after by gained solid filter, solid with ethyl acetate washes 2 times (generally every gram of unhindered amina 5-6mL), and solid dry (45 DEG C) 4 hours in vacuum drying oven that will obtain, namely relevant acylate is prepared。
Method two (acid is solid): by 5-(2-fluorophenyl)-N-first class-1-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia and ethyl acetate, isopropanol mixes, and under agitation dissolve (generally every gram of unhindered amina 4-8mL), at room temperature (10-25 DEG C), it is dissolved in ethanol by corresponding acid (generally every gram of unhindered amina 3-5mL, unhindered amina is 1:1.05 with corresponding sour mol ratio), it is added drop-wise in reaction system, and stir 30 minutes at such a temperature, after system temperature is down to 3-6 DEG C, stirring stirring 30 minutes, after by gained solid filter, solid with ethyl acetate washes 2 times (generally every gram of unhindered amina 5-6mL), and solid dry (45 DEG C) 4 hours in vacuum drying oven that will obtain, namely relevant acylate is prepared。
Method three (preparation of hydrochlorate): by 5-(2-fluorophenyl)-N-first class-1-(3-pyridine radicals semi-annular jade pendant acyl group)-1H-pyrroles's-3-first ammonia and ethyl acetate, isopropanol mixing (generally every gram of unhindered amina ethyl acetate 3mL, isopropanol 3mL), at room temperature (10-25 DEG C) stirring and dissolving, after system temperature is down to 3-6 DEG C, and pass into dried hydrogen chloride gas, and in these stable first stirring 2 hours, after by gained solid filter, solid with ethyl acetate washes 2 times (generally every gram of unhindered amina 5-6mL), and solid dry (45 DEG C) 4 hours in vacuum drying oven that will obtain.
The present invention has done the water solublity of the corresponding salt of Xiang Yingyou and has investigated, and particular content has:
Water solublity (does by Chinese Pharmacopoeia requirement); concrete operations: weigh the test sample being ground into fine powder or measure liquid test sample; in solvent as 25 DEG C ± 2 DEG C of certain capacities; every 5min brute force jolting 30s; observe the dissolving situation in 30min; as, during without visually visible particles of solute or drop, being namely considered as being completely dissolved。Dissolubility is with reference to following standard:
Very easily dissolve and mean that solute 1g (mL) can dissolve in solvent is less than 1mL；
Readily soluble mean that solute 1g (mL) can dissolve in solvent 1～less than 10mL；
Dissolving means that solute 1g (mL) can dissolve in solvent 10～less than 30mL；
Slightly molten mean that solute 1g (mL) can dissolve in solvent 30～less than 100mL
Slightly soluble means that solute lg (mL) can dissolve in solvent 100～less than 1000mL；
Soluble,very slightly means that solute 1g (mL) can dissolve in solvent 1000～less than 10000mL；
Almost insoluble or insoluble mean that solute 1g (mL) can not be completely dissolved in solvent 10000mL。
Shown in the partial salts compound of the present invention and TAK438 dissolubility contrast table 1 in water:
Table 1. partially salinated compound and TAK438 dissolubility in water
The study on the stability experiment of the compounds of this invention
1. influence factor's experiment: will wherein 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia acetate, 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia sulfate, 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia mesylate carries out influence factor's experiment respectively:
High temperature (40 DEG C), high temperature (60 DEG C) sampled at the 5th day and the 10th day respectively, and compound character is studied (color, dissolubility), had related substance and content with high performance liquid chromatograph detection。
High humidity (75%RH), high humidity (92.5%RH) sampled at the 5th day and the 10th day respectively, and compound character is studied (color, dissolubility), detected related substance and content with high performance liquid chromatograph。
Illumination (4500lx) sampled at the 5th day and the 10th day respectively, and compound character is studied (color, dissolubility), detected related substance and content with high performance liquid chromatograph。
2. Acceleration study (40 DEG C, 75%RH): sampled at 1st month, the 3rd month, the 6th month respectively, compound character is studied (color, dissolubility), detect related substance and content with high performance liquid chromatograph。
Found by the investigation of relevant stability: 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia acetate, 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia sulfate stability is better, it is possible to as the compound of research further。
5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia acetate crystal formation research。
The 5-(2-fluorophenyl that different batches is prepared)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia acetate carries out powder X-ray diffraction; obtain the crystalline structure of this compound, test condition: 40kv40mA slit: 1.0/1.0/Ni/0.1 step-length: 0.02 ° of target type: CuRange:3.00-40.00DegscanRate:10.00Deg/min。
Sweep limits is interval from 3 ° to 40 ° at 2 θ, and available from interval, the lattice plane d of the X-ray diffracting spectrum determined, following numerical value is range of error is the meansigma methods of ± 0.1:
5.62、6.20、7.62、8.80、10.05、11.01、11.50、12.90、14.07、14.89、16.15、16.52、
16.79、17.48、17.79、18.59、19.15、19.73、20.18、20.73、21.40、21.78、22.65、24.05、24.28
Interval, reflective display the strongest in X-ray diffracting spectrum following lattice plane:
2 θ [°]: 6.20,7.62,8.80,10.05,11.01,11.50,16.15,16.52,16.79,17.48
, 17.79,19.73,22.65, particularly: 7.62,10.05,11.01,16.79,17.48,17.79,19.73。
Beneficial effects of the present invention: by 5-(2-fluorophenyl) research of-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia soluble organic acid salt or inorganic acid salt compounds finds, 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia acetate and 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia acetate is at water solublity, stability aspect has relatively satisfactory performance, in changing dosage form, good candidate compound is provided for such medicine later, more have fast, the more effective effect playing treatment gastric acid related disease, meet different clinical application demands。
Detailed description of the invention
Following example are in order to illustrate the present invention, but not as limitation of the present invention。
Below with reference in embodiment, instrument:
Nuclear magnetic resonance analyser: Germany BRUKER500MHZ
Melting point apparatus: Shen light WRR, Shanghai precision instrument factory
High performance liquid chromatograph: Agilent 1260
Electronic balance: MettlerXS105
Vacuum drying oven: Shanghai Suo Pu instrument company vacuum drying oven DZF6021
Constant temperature humidity chamber:
X-ray diffractometer: BrukerD8AdvanceX x ray diffractometer x
Embodiment 1
5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia sulfate
In 100mL single port bottle, add 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles-3-first ammonia (5.0g, 14.48mmol) and ethyl acetate (25mL), and at room temperature (15 DEG C) stirring and dissolving, sulphuric acid (0.5mL is dripped in reaction system, 15.20mmol), stirring 30 minutes at such a temperature, add isopropanol (20mL), after cool the temperature to 3 DEG C, and stir 30 minutes, solid is had to precipitate out, solid is filtered out, and wash (10mL*2 time) by ethyl acetate, by obtained solid dry (45 DEG C) 4 hours in vacuum drying oven, obtain off-white color solid 4.3g, yield is 76%。
1HNMR(DMSO-d6;500MHZ)δ(ppm)8.89(dd,J=4.8,J=1.3,1H),8.72(s,2H),8.56(d,J=2.0,1H),7.92(dd,J=8.1,J=2.1,1H),7.84(s,1H),7.64(m,1H),7.52(m,1H),7.22(m,2H),7.10(m,1H),6.54(d,J=1.5,1H),4.04(s,2H),2.57(s,3H)
Embodiment 2
5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-tamaron hydrochlorate
In 100mL single port bottle, add 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles-3-first ammonia (3.0g, 6.1mmol) with ethyl acetate (15mL), and at room temperature (15 DEG C) stirring and dissolving, phosphoric acid (0.3mL is dripped in reaction system, 4.6mmol, 85%), stirring 30 minutes at such a temperature, add isopropanol (12mL), after cool the temperature to 2 DEG C, and stir 30 minutes, solid is had to precipitate out, solid is filtered out, and wash (8mL*2 time) by ethyl acetate, by obtained solid dry (45 DEG C) 4 hours in vacuum drying oven, obtain off-white color solid 3.1g, yield is 91.0%。
1HNMR(DMSO-d6;500MHZ)δ(ppm)8.86(d,J=4.6,1H),8.71(s,2H),8.55(d,J=1.9,1H),7.92(d,J=8.1,1H),7.83(s,1H),7.66(m,1H),7.53(m,1H),7.23(m,2H),7.11(m,1H),6.55(d,J=1.6,1H),3.92(s,2H),2.51(s,3H)
Embodiment 3
5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia mesylate
In 100mL single port bottle, add 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles-3-first ammonia (6.0g, 14.4mmol) and ethyl acetate (30mL), and at room temperature (15 DEG C) stirring and dissolving, methanesulfonic acid (1.2mL is dripped in reaction system, 18.3mmol), stirring 30 minutes at such a temperature, add isopropanol (20mL), after cool the temperature to 2 DEG C, and stir 30 minutes, solid is had to precipitate out, solid is filtered out, and wash (12mL*2 time) by ethyl acetate, by obtained solid dry (45 DEG C) 4 hours in vacuum drying oven, obtain off-white color solid 3.9g, yield is 55.8%。
1HNMR(DMSO-d6;500MHZ)δ(ppm)8.89(d,J=4.7,1H),8.75(s,2H),8.57(s,1H),7.90(d,J=8.0,1H),7.83(s,1H),7.64(m,1H),7.53(m,1H),7.23(m,2H),7.10(m,1H),6.52(s,2H),6.39(s,4H),4.02(t,2H),2.55(t,3H),2.44(brs,6H)
Embodiment 4
5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia acetate
In 100mL single port bottle, add 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles-3-first ammonia (3.0g, 8.7mmol) with ethyl acetate (15mL), and at room temperature (15 DEG C) stirring and dissolving, phosphoric acid (0.6mL is dripped in reaction system, 9.1mmol), stirring 30 minutes at such a temperature, add isopropanol (12mL), after cool the temperature to 2 DEG C, and stir 30 minutes, solid is had to precipitate out, solid is filtered out, and wash (8mL*2 time) by ethyl acetate, by obtained solid dry (45 DEG C) 4 hours in vacuum drying oven, obtain off-white color solid 1.6g, yield is 46%。
1HNMR(DMSO-d6;500MHZ)δ(ppm)8.85(d,J=4.8,1H),8.56(d,J=2.3,1H),7.87(d,J=8.1,1H),7.61(m,1H),7.50(m,1H),7.23(m,2H),7.13(m,1H),6.39(s,4H),3.53(s,2H),2.24(s,3H),1.86(s,3H)
Embodiment 5
5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia L MALIC ACID salt
In 50mL there-necked flask, add 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles-3-first ammonia (2.0g, 14.48mmol), ethyl acetate (6mL) and isopropanol (6mL), and at room temperature (15 DEG C) stirring and dissolving, heat to 50 DEG C to reaction system, add L MALIC ACID (0.82g, 6.1mmol), stirring 30 minutes at such a temperature, , after cool the temperature to (15 DEG C) under room temperature, and stir 10 minutes, after cool the temperature to 2 DEG C, and stir 30 minutes, solid is had to precipitate out, solid is filtered out, and wash (6mL*2 time) by ethyl acetate, by obtained solid dry (45 DEG C) 4 hours in vacuum drying oven, obtain working as yellow solid 1.5g, yield is 62%, it is very strong that this compound draws tide, Character instability in atmosphere。
1HNMR(DMSO-d6;500MHZ)δ(ppm)8.88(d,J=4.6,1H),8.73(s,2H),8.57(s,1H),7.91(d,J=8.1,1H),7.81(s,1H),7.63(m,1H),7.51(m,1H),7.21(m,2H),7.12(m,1H),6.50(s,1H),4.22(d,J=2.7,1H),3.88(s,2H),2.64(t,2H),(2.41(s,3H)
Embodiment 6
5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia citrate
In 50mL there-necked flask, add 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles-3-first ammonia (2.0g, 14.48mmol), ethyl acetate (6mL) and isopropanol (6mL), and at room temperature (15 DEG C) stirring and dissolving, heat to 50 DEG C to reaction system, add L MALIC ACID (0.82g, 6.1mmol), stirring 30 minutes at such a temperature, , after cool the temperature to (15 DEG C) under room temperature, and stir 10 minutes, after cool the temperature to 2 DEG C, and stir 30 minutes, solid is had to precipitate out, solid is filtered out, and wash (6mL*2 time) by ethyl acetate, by obtained solid dry (45 DEG C) 4 hours in vacuum drying oven, obtain working as yellow solid 1.4g, yield is 54%, it is very strong that this compound draws tide, Character instability in atmosphere。
1HNMR(DMSO-d6;500MHZ)δ(ppm)8.90(d,J=4.6,1H),8.73(s,2H),8.56(s,1H),7.93(d,J=8.0,1H),7.82(s,1H),7.62(m,1H),7.51(m,1H),7.22(m,2H),7.11(m,1H),6.50(s,1H),3.90(s,2H),2.63(s,2H),2.42(brs,3H)
Embodiment 7
5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia hydrochloric acid salt
In 100mL there-necked flask, add 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles-3-first ammonia (3.0g, 14.48mmol) and ethyl acetate (14mL), and at room temperature (15 DEG C) stirring and dissolving, after cool the temperature to 10 DEG C, dried hydrogen chloride gas is passed in reaction system, and stir 30 minutes, solid is had to precipitate out, solid is filtered out, and wash (10mL*2 time) by ethyl acetate, by obtained solid dry (45 DEG C) 4 hours in vacuum drying oven, obtain off-white color solid 1.2g, productivity is: 39%, it is very strong that this compound draws tide, Character instability in atmosphere。
1HNMR(DMSO-d6;500MHZ)δ(ppm)8.89(d,J=4.8,1H),8.73(s,2H),8.55(d,J=2.1,1H),7.92(d,J=8.1,1H),7.84(s,1H),7.64(m,1H),7.52(m,1H),7.22(m,2H),7.11(m,1H),6.53(d,J=1.5,1H),3.93(s,2H),2.48(s,3H)
Study on the stability embodiment
Example 1
5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia sulfate
1. influence factor's experiment:
High temperature (40 DEG C), high temperature (60 DEG C) sampled at the 5th day and the 10th day respectively, and compound character is studied (color, dissolubility), had related substance and content with high performance liquid chromatograph detection。
High humidity (75%RH), high humidity (92.5%RH) sampled at the 5th day and the 10th day respectively, and compound character is studied (color, dissolubility), detected related substance and content with high performance liquid chromatograph。
Illumination (4500lx) sampled at the 5th day and the 10th day respectively, and compound character is studied (color, dissolubility), detected related substance and content with high performance liquid chromatograph。
2. Acceleration study (40 DEG C, 75%RH):
Sampled at 1st month, the 3rd month, the 6th month respectively, compound character is studied (color, dissolubility), detect related substance and content with high performance liquid chromatograph。
By the data of this compound determination are analyzed discovery, this compound is tested in (5 days, 10 days) at the high humidity of influence factor, darkening, dissolubility is unchanged, (at 10 days in relevant substance-measuring, impurity increases, and mainly at t=8.66min, content is 0.26%), in Acceleration study, having new impurity to produce 1 month, 3 months, 6 middle of the month, when 6th month, assay only had 99.37%(impurity to exist respectively, t=16.18, t=31.92)。
Example 2
5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia mesylate
1. influence factor's experiment:
High temperature (40 DEG C), high temperature (60 DEG C) sampled at the 5th day and the 10th day respectively, and compound character is studied (color, dissolubility), had related substance and content with high performance liquid chromatograph detection。
High humidity (75%RH), high humidity (92.5%RH) sampled at the 5th day and the 10th day respectively, and compound character is studied (color, dissolubility), detected related substance and content with high performance liquid chromatograph。
Illumination (4500lx) sampled at the 5th day and the 10th day respectively, and compound character is studied (color, dissolubility), detected related substance and content with high performance liquid chromatograph。
2. Acceleration study (40 DEG C, 75%RH):
Sampled at 1st month, the 3rd month, the 6th month respectively, compound character is studied (color, dissolubility), detect related substance and content with high performance liquid chromatograph。
By the data of this compound determination are analyzed discovery, this compound is tested in (5 days, 10 days) at the high humidity of influence factor, color also has intensification, and dissolubility is unchanged, has related substance to have and increases (when 10 days, impurity increases, and mainly at t=7.56min, content is 0.17%)；Having new impurity to produce 1 month, 3 months, 6 middle of the month in Acceleration study, especially when 6th month, assay only has 99.60%(impurity to exist respectively, t=18.23, t=31.87；Content respectively 0.1%, 0.13%)。
Example 3
5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia acetate
1. influence factor's experiment:
High temperature (40 DEG C), high temperature (60 DEG C) sampled at the 5th day and the 10th day respectively, and compound character is studied (color, dissolubility), had related substance and content with high performance liquid chromatograph detection。High humidity (75%RH),
High humidity (92.5%RH) sampled at the 5th day and the 10th day respectively, and compound character is studied (color, dissolubility), detected related substance and content with high performance liquid chromatograph。
Illumination (4500lx) sampled at the 5th day and the 10th day respectively, and compound character is studied (color, dissolubility), detected related substance and content with high performance liquid chromatograph。
2. Acceleration study (40 DEG C, 75%RH):
Sampled at 1st month, the 3rd month, the 6th month respectively, compound character is studied (color, dissolubility), detect related substance and content with high performance liquid chromatograph。
By the data of this compound determination being analyzed discovery, this compound is in influence factor tests, character, content is also without significant change, have in the mensuration of related substance and generate without new impurity, 6 months Acceleration study test in, character is unchanged, content almost without change, have related substance not increase。
Claims (7)
1.5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia soluble organic acid salt or mineral acid
In formula, n is 1 or 1/2, HA is organic acid or mineral acid。
2. the 5-(2-fluorophenyl required according to right 1)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia soluble organic acid salt or mineral acid; it is characterized in that, its described organic acid or electrodeless acid is: acetic acid, methanesulfonic acid, sulphuric acid, phosphoric acid, L MALIC ACID, citric acid。
3. one kind with the 5-(2-fluorophenyl described in claim 2) the good salt of water solublity is respectively in-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia machine hydrochlorate or mineral acid: 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia acetate, 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia sulfate, 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia mesylate, 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia first citrate。
4. one kind with the 5-(2-fluorophenyl described in claim 3)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia acetate, 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia sulfate, 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia mesylate, 5-(2-fluorophenyl) in-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia first citrate, pass through study on the stability, wherein 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia acetate and 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia sulfate the two compound is more stable。
5. in requiring according to right 4, mention 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first ammonia acetate, this compound have be approximately in 7.62,10.05,11.01,16.79,17.48,17.79,19.73(2 θ) XRPD reflection。
6. in requiring according to right 4, mention 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridine radicals semi-annular jade pendant acyl group)-1H-pyrroles's-3-first ammonia acetate, the XRPD of this compound is such as shown in accompanying drawing one。
7. the present invention is used for erosive esophagitis, gastric ulcer, duodenal ulcer, helicobacter pylori eradication indication, and treats the relevant disease caused due to hyperchlorhydria。
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